Concerns regarding lamotrigine and breast-feeding☆
Introduction
Many women with epilepsy of childbearing age are treated with lamotrigine (LTG), resulting in a greater number of fetal exposures to the drug. The LTG Pregnancy Registry has been helpful in documenting results of fetal malformation due to in utero exposure to medication [1]. However, information regarding breast-feeding and the effects of longer exposure to drug from breast milk are limited.
The American Academy of Neurology recommends that women with epilepsy nurse their children [2]. These guidelines take into account the amount of drug in breast milk but little thought was given to measuring drug levels in the neonate. This may be particularly important when infants metabolize a drug poorly. Slow elimination leads to greater drug accumulation and increased potential risk of adverse effects.
LTG is extensively metabolized by hepatic glucuronidation, a major detoxification pathway in mammals, and is renally eliminated [3]. The major metabolite in humans (70% of the total dose) is N-2 glucuronide conjugate. The enzyme responsible for the reaction is uridine 5′-diphosphate (UDP) glucuronosyl transferase (UDPGT). UDPGT is species specific and varies widely in substrate specificity. There are many factors that affect glucuronidation including smoking, diet, concomitant drugs, ethnicity, disease states, hormones, genetics, and, importantly, age.
This paper focuses on the effect of age on glucuronidation and reviews LTG levels in newborns born to nursing mothers with epilepsy on monotherapy.
Section snippets
Methods
Nursing mothers with epilepsy on LTG monotherapy and their babies were evaluated. Serum LTG levels were obtained from the neonates beginning on Day 10 of life. Simultaneous maternal LTG levels were obtained. LTG clearance during pregnancy was calculated for each trimester of pregnancy and the postpartum period when available. It was compared with preconception LTG clearance. Clearance was calculated when LTG dose, LTG serum level and patient weight were known according to the formula: clearance
Results
All four subjects had partial epilepsy. Age range was 26–33 years (mean, 29 years). Epilepsy onset was 7–24 years (mean, 16 years) and monthly seizure frequency was 0–6 (mean, 1.5). Three patients were seizure-free and one subject had six simple partial seizures each month. Daily LTG doses were 150–525 mg/day (mean, 338 mg) before conception and 200–1000 mg/day (mean, 612 mg) at delivery. Doses were adjusted during pregnancy when clinically indicated based on serum medication levels or change in
Discussion
Serum concentrations of LTG in these breast-fed children were higher than expected based on the small amounts ingested from breast milk. In some cases, the levels were in the same range as concentrations found in patients who receive much larger therapeutic LTG doses. Overall, levels were 30% of maternal drug levels.
At term, most antiepileptic drugs (AEDs) are present in neonatal plasma in concentrations similar to those in maternal plasma [4]. Levels in nursing children, as they age, are
References (16)
Drug metabolism in pregnancy, infancy and childhood
Pharmacol. Ther.
(1987)- et al.
International Lamotrigine Pregnancy registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine
Epilepsia
(2002) - Practice Parameter: Management issues for women with epilepsy (summary statement). Report of the Quality Standards...
- et al.
Lamotrigine: chemistry and biotransformation
- et al.
Anticonvulsants during pregnancy and lactation: transplacental, maternal, and neonatal pharmacokinetics
Clin. Pharmacokinet.
(1982) - et al.
Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child
Eur. J. Clin. Pharmacol.
(1997) - et al.
Drug glucuronidation in humans
Pharmacol. Ther.
(1999) - et al.
The inadequacy of perinatal glucuronidation: immunoblast analysis of the developmental expression of individual UDP-glucuronosyltransferase isoenzymes in rat and human liver microsomes
Mol. Pharmacol.
(1988)
Cited by (76)
Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period
2022, Biomedicine and PharmacotherapyCitation Excerpt :Free transplacental passage of LTG with an umbilical cord/maternal serum concentration ratio close to 1.0 has previously been confirmed, and the exposure of LTG in breastfed newborns is lower than that during pregnancy [4,7,11–27]. However, with the exception of the study by Paulzen et al. [19], in which concentrations of LTG were measured in colostrum, all existing studies were performed at least one week after delivery [4,7,13,15–18,20–27]. To the best of our knowledge, a simultaneously analysis of LTG concentrations measured in maternal serum, colostrum, and serum of breastfed newborns during the first postnatal week has not yet been performed.
Examples of Drugs With Poor Oral Bioavailability
2017, Fetal and Neonatal Physiology, 2-Volume SetMood stabilizers and antipsychotics during breastfeeding: Focus on bipolar disorder
2016, European NeuropsychopharmacologyCitation Excerpt :Its efficacy for the treatment of bipolar depression is still under debate (Reinares et al., 2014). The evidence on the safety of the treatment with LTG during breastfeeding derives from one naturalistic, three open studies and various case reports and series, reporting high variability in infants’ plasma concentrations and in M/P ratios but no serious adverse effects or cognitive and development alterations (Meador et al., 2010, 2014; Veiby et al., 2013; Tomson et al., 1997; Rambeck et al., 1997; Ohman et al., 2000; Liporace et al., 2004; Gentile, 2005; Page-Sharp et al., 2006; Newport et al., 2008; Fotopoulou et al., 2009), with the exception of elevated platelet counts in 7 out of 8 children without clinical consequences (Newport et al., 2008), a case of mild apnea and cyanosis with therapeutic values of LTG of 4.9 μg/ml in infant׳s serum (Nordmo et al., 2009) and another case of an intermittently occurring skin rash of little clinical relevance (Wakil et al., 2009) (Table 1). During the last years, an increased number of studies have supported the use of antipsychotics (APs)- especially second generation APs- as a valid therapeutic alternative for the treatment of BD, both as monotherapy and as adjunctive treatment to traditional mood stabilizers (Vieta et al., 2008a, 2008b, 2010, 2011; Yildiz et al., 2011) (Table 2).
Antiepileptics
2015, Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment: Third EditionDevelopmental neurotoxicity and anticonvulsant drugs: A possible link
2014, Reproductive ToxicologyNew antiepileptic drugs and women
2014, SeizureCitation Excerpt :Indeed, it has been suggested that full UGT1A4 activity may not be reached before almost 19 years of age.90 In sum, over 50 mother/infant pairs have been documented so far.66,68–70,87,88,91–95 With only one exception, no adverse effects have been noted in these studies.
- ☆
Presented at the American Epilepsy Society meeting, December 2003.